SUMMARY OF PRODUCT CHARACTERISTICS

Transcription

1 SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT Targinact 2.5 mg/1.25 mg prolonged-release tablets Targinact 15 mg/7.5 mg prolonged-release tablets Targinact 30 mg/15 mg prolonged-release tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION {Targinact 2.5 mg/1.25 mg} Each prolonged-release tablet contains 2.5 mg of oxycodone hydrochloride equivalent to 2.25 mg oxycodone and 1.25 mg naloxone hydrochloride as 1.37 mg of naloxone hydrochloride dihydrate equivalent to 1.13 mg naloxone. {Targinact 15 mg/7.5 mg} Each prolonged-release tablet contains 15 mg of oxycodone hydrochloride equivalent to 13.5 mg oxycodone and 7.5 mg naloxone hydrochloride as 8.24 mg of naloxone hydrochloride dihydrate equivalent to 6.75 mg naloxone. {Targinact 30 mg/15 mg} Each prolonged-release tablet contains 30 mg of oxycodone hydrochloride equivalent to 27 mg oxycodone and 15 mg naloxone hydrochloride as mg of naloxone hydrochloride dihydrate equivalent to 13.5mg naloxone {Targinact 2.5 mg/1.25 mg} Excipient with known effect: Each prolonged-release tablet contains 34.1 mg lactose anhydrous {Targinact 15 mg/7.5 mg} Excipient with known effect: Each prolonged-release tablet contains 53.0 mg lactose anhydrous {Targinact 30 mg/15 mg} Excipient with known effect: Each prolonged-release tablet contains 36.5 mg lactose anhydrous For the full list of excipients, see section PHARMACEUTICAL FORM Prolonged-release tablet {Targinact 2.5 mg/1.25 mg} Light yellow, round tablets, 5mm in size, with a film coating. {Targinact 15 mg/7.5 mg} Grey, oblong tablets, with a nominal length of 9.5mm and with a film coating, embossed OXN on one side and 15 on the other. {Targinact 30 mg/15 mg} Brown, oblong tablets, with a nominal length of 9.5mm and with a film coating, embossed OXN on one side and 30 on the other. Versie 1 juni 2016 Pagina 1 van 15

2 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Severe pain, which can be adequately managed only with opioid analgesics. The opioid antagonist naloxone is added to counteract opioid-induced constipation by blocking the action of oxycodone at opioid receptors locally in the gut. Targinact is indicated in adults. 4.2 Posology and method of administration Posology The analgesic efficacy of Targinact is equivalent to oxycodone hydrochloride prolonged-release formulations. The dosage should be adjusted to the intensity of pain and the sensitivity of the individual patient. Unless otherwise prescribed, these tablets should be administered as follows: Adults The usual starting dose for an opioid naïve patient is 10 mg/5 mg of oxycodone hydrochloride/naloxone hydrochloride at 12 hourly intervals. Lower strengths are available to facilitate dose titration when initiating opioid therapy and for individual dose adjustment. Patients already receiving opioids may be started on higher doses depending on their previous opioid experience. The maximum daily dose of these tablets is 160 mg oxycodone hydrochloride and 80 mg naloxone hydrochloride. The maximum daily dose is reserved for patients who have previously been maintained on a stable daily dose and who have become in need of an increased dose. Special attention should be given to patients with compromised renal function and patients with mild hepatic impairment if an increased dose is considered. For patients requiring higher doses, administration of supplemental prolonged-release oxycodone hydrochloride at the same time intervals should be considered, taking into account the maximum daily dose of 400 mg prolonged-release oxycodone hydrochloride. In the case of supplemental oxycodone hydrochloride dosing, the beneficial effect of naloxone hydrochloride on bowel function may be impaired. After complete discontinuation of therapy with these tablets with a subsequent switch to another opioid a worsening of the bowel function can be expected. Some patients taking these prolonged-release tablets according to a regular time schedule require immediaterelease analgesics as "rescue" medication for breakthrough pain. Targinact is a prolonged-release formulation and therefore not intended for the treatment of breakthrough pain. For the treatment of breakthrough pain, a single dose of rescue medication should approximate one sixth of the equivalent daily dose of oxycodone hydrochloride. The need for more than two rescues per day is usually an indication that the dosage requires upward adjustment. This adjustment should be made every 1-2 days in steps of 5 mg/2.5 mg twice daily, or where necessary 2.5 mg/1.25 mg or 10 mg/5 mg, oxycodone hydrochloride/naloxone hydrochloride until a stable dose is reached. The aim is to establish a patient-specific twice daily dose that will maintain adequate analgesia and make use of as little rescue medication as possible for as long as pain therapy is necessary. Slightly elevated (dose corrected) peak plasma concentrations should be taken into account when the 2.5mg/1.25 mg tablet is used (see section 5.2). Versie 1 juni 2016 Pagina 2 van 15

3 Targinact is taken at the determined dosage twice daily according to a fixed time schedule. While symmetric administration (the same dose mornings and evenings) subject to a fixed time schedule (every 12 hours) is appropriate for the majority of patients, some patients, depending on the individual pain situation, may benefit from asymmetric dosing tailored to their pain pattern. In general, the lowest effective analgesic dose should be selected. In non-malignant pain therapy, daily doses of up to 40 mg/20 mg oxycodone hydrochloride/naloxone hydrochloride are usually sufficient, but higher doses may be needed. For doses not realisable/practicable with this strength other strengths of this medicinal product are available. Elderly patients As for younger adults the dosage should be adjusted to the intensity of the pain and the sensitivity of the individual patient. Patients with impaired hepatic function A clinical trial has shown that plasma concentrations of both oxycodone and naloxone are elevated in patients with hepatic impairment. Naloxone concentrations were affected to a higher degree than oxycodone (see section 5.2). The clinical relevance of a relative high naloxone exposure in hepatic impaired patients is yet not known. Caution must be exercised when administering these tablets to patients with mild hepatic impairment (see section 4.4). In patients with moderate and severe hepatic impairment Targinact is contraindicated (see section 4.3). Patients with impaired renal function A clinical trial has shown that plasma concentrations of both oxycodone and naloxone are elevated in patients with renal impairment (see section 5.2). Naloxone concentrations were affected to a higher degree than oxycodone. The clinical relevance of a relative high naloxone exposure in renal impaired patients is yet not known. Caution should be exercised when administering these tablets to patients with renal impairment (see section 4.4). Paediatric population The safety and efficacy of Targinact in children aged below 18 years has not been established. No data are available Method of administration Oral use. These prolonged-release tablets are taken in the determined dosage twice daily in a fixed time schedule. The prolonged-release tablets may be taken with or without food with sufficient liquid. These tablets must be swallowed whole, and not broken, chewed or crushed (see section 4.4). Duration of use These tablets should not be administered for longer than absolutely necessary. If long-term pain treatment is necessary in view of the nature and severity of the illness, careful and regular monitoring is required to establish whether and to what extent further treatment is necessary. When the patient no longer requires opioid therapy, it may be advisable to taper the dose gradually (see section 4.4). Versie 1 juni 2016 Pagina 3 van 15

4 4.3 Contraindications Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, Severe respiratory depression with hypoxia and/or hypercapnia, Severe chronic obstructive pulmonary disease, Cor pulmonale, Severe bronchial asthma, Non-opioid induced paralytic ileus, Moderate to severe hepatic impairment. 4.4 Special warnings and precautions for use The major risk of opioid excess is respiratory depression. Caution must be exercised when administering these tablets to elderly or infirm patients, patients with opioid-induced paralytic ileus, patients presenting severely impaired pulmonary function, myxoedema, hypothyroidism, Addison s disease (adrenal cortical insufficiency), toxic psychosis, cholelithiasis, prostate hypertrophy, alcoholism, delirium tremens, pancreatitis, hypotension, hypertension, pre-existing cardiovascular diseases, head injury (due to the risk of increased intracranial pressure), epileptic disorder or predisposition to convulsions, or patients taking MAO inhibitors. Caution must also be exercised when administering these tablets to patients with mild hepatic or renal impairment. Careful medical monitoring is particularly necessary for patients with severe renal impairment. Diarrhoea may be considered as a possible effect of naloxone. In patients under long-term opioid treatment the switch to Targinact can initially provoke withdrawal symptoms. Such patients may require specific attention. Targinact is not suitable for the treatment of withdrawal symptoms. During long-term administration, the patient may develop tolerance to the medicinal product and require higher doses to maintain the desired effect. Chronic administration of these tablets may lead to physical dependence. Withdrawal symptoms may occur upon the abrupt cessation of therapy. If therapy is no longer required, it may be advisable to reduce the daily dose gradually in order to avoid the occurrence of withdrawal syndrome (see section 4.2). There is potential for development of psychological dependence (addiction) to opioid analgesics, including Targinact. These tablets should be used with particular care in patients with a history of alcohol and drug abuse. Oxycodone alone has an abuse profile similar to other strong agonist opioids. In order not to impair the prolonged-release characteristic of the prolonged-release tablets, the prolongedrelease tablets must be taken whole and must not be broken, chewed or crushed. Breaking, chewing or crushing the prolonged-release tablets for ingestion leads to a faster release of the active substances and the absorption of a possibly fatal dose of oxycodone (see section 4.9). Concomitant use of alcohol and Targinact may increase the undesirable effects of Targinact; concomitant use should be avoided. Studies have not been performed on the safety and efficacy of Targinact in children and adolescents below the age of 18 years. Therefore, their use in children and adolescents under 18 years of age is not recommended. There is no clinical experience in patients with cancer associated to peritoneal carcinomatosis or with subocclusive syndrome in advanced stages of digestive and pelvic cancers. Therefore, the use of these tablets in this population is not recommended. Versie 1 juni 2016 Pagina 4 van 15

5 These tablets are not recommended for pre-operative use or within the first hours post-operatively. Depending on the type and extent of surgery, the anaesthetic procedure selected, other co-medication and the individual condition of the patient, the exact timing for initiating post-operative treatment with <these tablets depends on a careful risk-benefit assessment for each individual patient. Any abuse of these tablets by drug addicts is strongly discouraged. If abused parenterally, intranasally or orally by individuals dependent on opioid agonists, such as heroin, morphine, or methadone, these tablets are expected to produce marked withdrawal symptoms - because of the opioid receptor antagonist characteristics of naloxone - or to intensify withdrawal symptoms already present (see section 4.9). These tablets consist of a dual-polymer matrix, intended for oral use only. Abusive parenteral injections of the prolonged-release tablet constituents (especially talc) can be expected to result in local tissue necrosis and pulmonary granulomas or may lead to other serious, potentially fatal undesirable effects. The empty prolonged-release tablet matrix may be visible in the stool. The use of Targinact may produce positive results in doping controls. The use of Targinact as a doping agent may become a health hazard. This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take Targinact. 4.5 Interaction with other medicinal products and other forms of interaction Substances having a CNS-depressant effect (e.g. other opioids, sedatives, hypnotics, anti-depressants, sleeping aids, phenothiazines, neuroleptics, anti-histamines and anti-emetics) may enhance the CNSdepressant effect (e.g. respiratory depression) of Targinact. Alcohol may enhance the pharmacodynamic effects of Targinact; concomitant use should be avoided. Clinically relevant changes in International Normalized Ratio (INR or Quick-value) in both directions have been observed in individuals if oxycodone and coumarin anticoagulants are co-applied. Oxycodone is metabolised primarily via the CYP3A4 pathways and partly via the CYP2D6 pathway (see section 5.2). The activities of these metabolic pathways may be inhibited or induced by various coadministered drugs or dietary elements. Targinact doses may need to be adjusted accordingly. CYP3A4 inhibitors, such as macrolide antibiotics (e.g. clarithromycin, erythromycin, telithromycin), azole-antifungal agents (e.g. ketoconazole, voriconazole, itraconazole, posaconazole), protease inhibitors (e.g. ritonavir, indinavir, nelfinavir, saquinavir), cimetidine and grapefruit juice may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations.a reduction in the dose of these tablets and subsequent re-titration may be necessary. CYP3A4 inducers, such as rifampicin, carbamazepine, phenytoin and St. John's Wort, may induce the metabolism of oxycodone and cause increased clearance of the drug, resulting in a decrease in oxycodone plasma concentrations. Caution is advised and further titration may be necessary to reach an adequate level of pain control. Theoretically,medicinal products that inhibit CYP2D6 activity, such as paroxetine, fluoxetine and quinidine, may cause decreased clearance of oxycodone which could lead to an increase in oxycodone plasma concentrations. Concomitant administration with CYP2D6 inhibitors hadan insignificant effect on the elimination of oxycodone and also had noinfluence on the pharmacodynamic effects of oxycodone. Versie 1 juni 2016 Pagina 5 van 15

6 In vitro metabolism studies indicate that no clinically relevant interactions are to be expected between oxycodone and naloxone. The likelihood of clinically relevant interactions between paracetamol, acetylsalicylic acid or naltrexone and the combination of oxycodone and naloxone in therapeutic concentrations is minimal. 4.6 Fertility, pregnancy and lactation Pregnancy There are no data from the use of Targinact in pregnant women and during childbirth. Limited data on the use of oxycodone during pregnancy in humans reveal no evidence of an increased risk of congenital abnormalities. For naloxone, insufficient clinical data on exposed pregnancies are available. However, systemic exposure of the women to naloxone after use of these tablets is relatively low (see section 5.2). Both oxycodone and naloxone pass into the placenta. Animal studies have not been performed with oxycodone and naloxone in combination (see section 5.3). Animal studies with oxycodone or naloxone administered as single drugs have not revealed any teratogenic or embryotoxic effects. Long-term administration of oxycodone during pregnancy may lead to withdrawal symptoms in the newborn. If administered during childbirth, oxycodone may evoke respiratory depression in the newborn. These tablets should only be used during pregnancy if the benefit outweighs the possible risks to the unborn child or neonate. Breastfeeding Oxycodone passes into the breast milk. A milk-plasma concentration ratio of 3.4:1 was measured and oxycodone effects in the suckling infant are therefore conceivable. It is not known whether naloxone also passes into the breast milk. However, after taking these tablets systemic naloxone levels are very low (see section 5.2). A risk to the suckling child cannot be excluded in particular following intake of multiple doses of these tablets by the breast-feeding mother. Breastfeeding should be discontinued during treatment with Targinact. Fertility There are no data with respect to fertility. 4.7 Effects on ability to drive and use machines Targinact has moderate influence on the ability to drive and use machines. This is particularly likely at the beginning of treatment, after dose increase or product rotation and if these tablets are combined with other CNS depressant agents. Patients stabilised on a specific dosage will not necessarily be restricted. Therefore, patients should consult with their physician as to whether driving or the use of machinery is permitted. 4.8 Undesirable effects The following frequencies are the basis for assessing undesirable effects: Very common ( 1/10) Common ( 1/100 to 1/10) Uncommon ( 1/1,000 to 1/100) Versie 1 juni 2016 Pagina 6 van 15

7 Rare (> 1/10,000 to 1/1,000) Very rare ( 1/10,000) Not known (cannot be estimated from the available data) Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Immune system disorders Uncommon: Hypersensitivity Metabolism and nutrition disorders Common: Decreased appetite up to loss of appetite Psychiatric disorders Common: Insomnia Uncommon: Abnormal thinking, anxiety, confusional state, depression, libido decreased, nervousness, restlessness Not known: Euphoric mood, hallucination, nightmares Nervous system disorders Common: Dizziness, headache, somnolence Uncommon: Convulsions (particularly in persons with epileptic disorder or predisposition to convulsions), disturbance in attention, dysgeusia, speech disorder, syncope, tremor, lethargy Not known: Paraesthesia, sedation Eye disorders Uncommon: Visual impairment Ear and labyrinth disorders Common: Vertigo Cardiac disorders Uncommon: Angina pectoris in particular in patients with history of coronary artery disease, palpitations Rare: Tachycardia Vascular disorders Common: Hot flush Uncommon: Blood pressure decreased, blood pressure increased Respiratory, thoracic and mediastinal disorders Uncommon: Dyspnoea, rhinorrhoea, cough Rare: Yawning Not known: Respiratory depression Gastrointestinal disorders Common: Abdominal pain, constipation, diarrhoea, dry mouth, dyspepsia, vomiting, nausea, flatulence Uncommon: Abdominal distension Rare: Tooth disorder Not known: Eructation Hepatobiliary disorders Uncommon: Hepatic enzymes increased, biliary colic Versie 1 juni 2016 Pagina 7 van 15

8 Skin and subcutaneous tissue disorders Common: Pruritus, skin reactions, hyperhidrosis Musculoskeletal and connective tissue disorders Uncommon: Muscle spasms, muscle twitching, myalgia Renal and urinary disorders Uncommon: Micturition urgency Not known: Urinary retention Reproductive system and breast disorders Not known: Erectile dysfunction General disorders and administration site conditions Common: Asthenia, fatigue Uncommon: Chest pain, chills, drug withdrawal syndrome, malaise, pain, peripheral oedema, thirst, Investigations Uncommon: Rare: Weight decreased Weight increased Injury, poisoning and procedural complications Uncommon: Injuries from accidents For the active substance oxycodone hydrochloride, the following additional undesirable effects are known: Due to its pharmacological properties, oxycodone hydrochloride may cause respiratory depression, miosis, bronchial spasm and spasms of nonstriated muscles as well as suppress the cough reflex. Infections and infestations Rare: Herpes simplex Immune system disorders Not known: Anaphylactic responses Metabolism and nutrition disorders Uncommon: Dehydration Rare: Increased appetite Psychiatric disorders Common: Altered mood and personality change, decreased activity, psychomotor hyperactivity Uncommon: Agitation, perception disturbances (e.g. derealisation), drug dependence Not known: Aggression Nervous system disorders Uncommon: Concentration impaired, migraine, hypertonia, involuntary muscle contractions, hypoaesthesia, abnormal coordination Not known: Hyperalgesia Ear and labyrinth disorders Uncommon: Hearing impaired Vascular disorders Versie 1 juni 2016 Pagina 8 van 15

9 Uncommon: Vasodilatation Respiratory, thoracic and mediastinal disorders Uncommon: Dysphonia Gastrointestinal disorders Common: Hiccups Uncommon: Dysphagia, ileus, mouth ulceration, stomatitis Rare: Melaena, gingival bleeding Not known: Dental caries Hepatobiliary disorders Not known: Cholestasis Skin and subcutaneous tissue disorders Uncommon: Dry skin Rare: Urticaria Renal and urinary disorders Common: Dysuria Reproductive system and breast disorders Uncommon: Hypogonadism Not known: Amenorrhoea General disorders and administration site conditions Uncommon: Oedema, drug tolerance Not known: Drug withdrawal syndrome neonatal Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 4.9 Overdose Symptoms of intoxication Depending on the history of the patient, an overdose of Targinact may be manifested by symptoms that are either triggered by oxycodone (opioid receptor agonist) or by naloxone (opioid receptor antagonist). Symptoms of oxycodone overdose include miosis, respiratory depression, somnolence progressing to stupor, hypotonia, bradycardia as well as hypotension. Coma, non-cardiogenic pulmonary oedema and circulatory failure may occur in more severe cases and may lead to a fatal outcome. Symptoms of a naloxone overdose alone are unlikely. Therapy of intoxication Withdrawal symptoms due to an overdose of naloxone should be treated symptomatically in a closelysupervised environment. Clinical symptoms suggestive of an oxycodone overdose may be treated by the administration of opioid antagonists (e.g. naloxone hydrochloride mg intravenously). Administration should be repeated at 2-3 minute intervals, as clinically necessary. It is also possible to apply an infusion of 2 mg naloxone hydrochloride in 500 ml of 0.9% sodium chloride or 5% dextrose (0.004 mg/ml naloxone). The infusion should be run at a rate aligned to the previously administered bolus doses and to the patient's response. Versie 1 juni 2016 Pagina 9 van 15

10 Consideration may be given to gastric lavage. Supportive measures (artificial ventilation, oxygen, vasopressors and fluid infusions) should be employed, as necessary, to manage the circulatory shock accompanying an overdose. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. Artificial ventilation should be applied if necessary. Fluid and electrolyte metabolism should be maintained. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Analgesics; Opioids; Natural opium alkaloids ATC code: N02AA55 Mechanism of action Oxycodone and naloxone have an affinity for mu, kappa and delta opiate receptors in the brain, spinal cord and peripheral organs (e.g. intestine). Oxycodone acts as opioid-receptor agonist at these receptors and affects pain relief by binding to the endogenous opioid receptors in the CNS. By contrast, naloxone is a pure antagonist acting on all types of opioid receptors. Pharmacodynamic effects Because of the pronounced first-pass metabolism, the bioavailability of naloxone upon oral administration is < 3%, therefore a clinically relevant systemic effect is unlikely. Due to the local competitive antagonism of the opioid receptor mediated oxycodone effect by naloxone in the gut, naloxone reduces the bowel function disorders that are typical for opioid treatment. Clinical efficacy and safety In a 12-week parallel group double-blinded study in 322 patients with opioid-induced constipation, patients who were treated with oxycodone hydrochloride - naloxone hydrochloride had on average one extra complete spontaneous (without laxatives) bowel movement in the last week of treatment, compared to patients who continued using similar doses of oxycodone hydrochloride prolonged release tablets (p<0.0001). The use of laxatives in the first four weeks was significantly lower in the oxycodonenaloxone group compared to the oxycodone monotherapy group (31% versus 55%, respectively, p<0.0001). Similar results were shown in a study with 265 non-cancer patients comparing daily doses of oxycodone hydrochloride/naloxone hydrochloride of 60 mg/30 mg to up to 80 mg/40 mg with oxycodone hydrochloride monotherapy in the same dose range. Opioids can influence the hypothalamic-pituitary-adrenal or gonadal axes. Among the changes observed are an increase of prolactin in the serum and a reduced level of cortisol and testosterone in the plasma. Clinical symptoms may occur because of these hormone changes. Preclinical studies show differing effects of natural opioids on components of the immune system. The clinical significance of these findings is not known. It is not known whether oxycodone, a semi-synthetic opioid, has similar effects on the immune system to natural opioids. 5.2 Pharmacokinetic properties Oxycodone hydrochloride Absorption Oxycodone has a high absolute bioavailability of up to 87% following oral administration. Distribution Following absorption, oxycodone is distributed throughout the entire body. Approximately 45% is bound to plasma protein. Oxycodone crosses the placenta and may be detected in breast milk. Versie 1 juni 2016 Pagina 10 van 15

11 Biotransformation Oxycodone is metabolised in the gut and the liver to noroxycodone and oxymorphone and to various glucuronide conjugates. Noroxycodone, oxymorphone and noroxymorphone are produced via the cytochrome P450 system. Quinidine reduces the production of oxymorphone in man without substantially influencing the pharmacodynamics of oxycodone. The contribution of the metabolites to overall pharmacodynamic effect is insignificant. Elimination Oxycodone and its metabolites are excreted in both urine and faeces. Naloxone hydrochloride Absorption Following oral administration, naloxone has a very low systemic availability of <3%. Distribution Naloxone passes into the placenta. It is not known, whether naloxone also passes into breast milk. Biotransformation and Elimination After parenteral administration, the plasma half-life is approximately one hour. The duration of action depends upon the dose and route of administration, intramuscular injection producing a more prolonged effect than intravenous doses. It is metabolised in the liver and excreted in the urine. The principal metabolites are naloxone glucuronide, 6 -Naloxol and its glucuronide. Oxycodone hydrochloride/ naloxone hydrochloride combination (Targinact) Pharmacokinetic/pharmacodynamic relationships The pharmacokinetic characteristics of oxycodone from Targinact is equivalent to those of prolongedrelease oxycodone hydrochloride tablets administered together with prolonged-release naloxone hydrochloride tablets. Tablets of various dose strengths may be combined when tailoring individual doses according to the patient s analgesic requirements and tolerability. If dose strengths are interchanged, however, it should be borne in mind that for the 2.5 mg/1.25 mg strength the dose-corrected Cmax is slightly higher (by 27.6%) than that associated with the reference 40 mg/20 mg. This compares with other strengths where the dosecorrected Cmax values from the 15 mg/7.5 mg and 30 mg/15 mg tablets are 18.6% and 18.7% higher than the reference. After the oral administration of Targinact in maximum dose to healthy subjects, the plasma concentrations of naloxone are so low that it is not feasible to carry out a pharmacokinetic analysis. To conduct a pharmacokinetic analysis naloxone-3-glucuronide as surrogate marker is used, since its plasma concentration is high enough to measure. Overall, following ingestion of a high-fat breakfast, the bioavailability and peak plasma concentration (C max ) of oxycodone were increased by an average of 16% and 30% respectively compared to administration in the fasting state. This was evaluated as clinically not relevant, therefore Targinact prolonged-release tablets may be taken with or without food (see section 4.2). In vitro drug metabolism studies have indicated that the occurrence of clinically relevant interactions involving Targinact is unlikely. Elderly patients Oxycodone For AUC of oxycodone, on average there was an increase to 118% (90% C.I.: 103, 135), for elderly compared with younger volunteers. For C max of oxycodone, on average there was an increase to 114% (90% C.I.: 102, 127). For C min of oxycodone, on average there was an increase to 128% (90% C.I.: 107, 152). Versie 1 juni 2016 Pagina 11 van 15

12 Naloxone For AUC of naloxone, on average there was an increase to 182% (90% C.I.: 123, 270), for elderly compared with younger volunteers. For C max of naloxone, on average there was an increase to 173% (90% C.I.: 107, 280). For C min of naloxone, on average there was an increase to 317% (90% C.I.: 142, 708). Naloxone-3-glucuronide For AUC of naloxone-3-glucuronide, on average there was an increase to 128% (90% C.I.: 113, 147), for elderly compared with younger volunteers. For C max of naloxone-3-glucuronide, on average there was an increase to 127% (90% C.I.: 112, 144). For C min of naloxone-3-glucuronide, on average there was an increase to 125% (90% C.I.: 105, 148). Patients with impaired hepatic function Oxycodone For AUC INF of oxycodone, on average there was an increase to 143% (90% C.I.: 111, 184), 319% (90% C.I.: 248, 411) and 310% (90% C.I.: 241, 398) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For C max of oxycodone, on average there was an increase to 120% (90% C.I.: 99, 144), 201% (90% C.I.: 166, 242) and 191% (90% C.I.: 158, 231) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For t 1/2Z of oxycodone, on average there was an increase to 108% (90% C.I.: 70, 146), 176% (90% C.I.: 138, 215) and 183% (90% C.I.: 145, 221) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. Naloxone For AUC of naloxone, on average there was an increase to 411% (90% C.I.: 152, 1112), 11518% (90% C.I.: 4259, 31149) and 10666% (90% C.I.: 3944, 28847) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For C max of naloxone, on average there was an increase to 193% (90% C.I.: 115, 324), 5292% (90% C.I: 3148, 8896) and 5252% (90% C.I.: 3124, 8830) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. Due to insufficient amount of data available t 1/2Z and the corresponding AUC INF of naloxone were not calculated. The bioavailability comparisons for naloxone were therefore based on AUC values. Naloxone-3-glucuronide For AUC INF of naloxone-3-glucuronide, on average there was an increase to 157% (90% C.I.: 89, 279), 128% (90% C.I.: 72, 227) and 125% (90% C.I.: 71, 222) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For C max of naloxone-3-glucuronide, on average there was an increase to 141% (90% C.I.: 100, 197), 118% (90% C.I.: 84, 166) and a decrease to 98% (90% C.I.: 70, 137) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. For t 1/2Z of naloxone-3-glucuronide, on average there was an increase to 117% (90% C.I.: 72, 161), a decrease to 77% (90% C.I.: 32, 121) and a decrease to 94% (90% C.I.: 49, 139) for mild, moderate and severe hepatically impaired subjects, respectively, compared with healthy volunteers. Patients with impaired renal function Oxycodone For AUC INF of oxycodone, on average there was an increase to 153% (90% C.I.: 130, 182), 166% (90% C.I.: 140, 196) and 224% (90% C.I.: 190, 266) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers. For C max of oxycodone, on average there was an increase to 110% (90% C.I.: 94, 129), 135% (90% C.I.: 115, 159) and 167% (90% C.I.: 142, 196) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers. For t 1/2Z of oxycodone, on average there was an increase to 149%, 123% and 142% for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers. Naloxone Versie 1 juni 2016 Pagina 12 van 15

13 For AUC t of naloxone, on average there was an increase to 2850% (90% C.I.: 369, 22042), 3910% (90% C.I.: 506, 30243) and 7612% (90% C.I.: 984, 58871) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers. For C max of naloxone, on average there was an increase to 1076% (90% C.l.: 154, 7502), 858% (90% C.I.: 123, 5981) and 1675% (90% C.I.: 240, 11676) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy volunteers. Due to insufficient amount of data available t 1/2Z and the corresponding AUC INF of naloxone were not calculated. The bioavailability comparisons for naloxone were therefore based on AUC t values. The ratios may have been influenced by the inability to fully characterize the naloxone plasma profiles for the healthy subjects. Naloxone-3-glucuronide For AUC INF of naloxone-3-glucuronide, on average there was an increase to 220% (90% C.I.: 148, 327), 370% (90% C.I.: 249, 550) and 525% (90% C.I.: 354, 781) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy subjects. For C max of naloxone-3-glucuronide, on average there was an increase to 148% (90% C.I.: 110, 197), 202% (90% C.I.: 151, 271) and 239% (90% C.I.: 179, 320) for mild, moderate and severe renally impaired subjects, respectively, compared with healthy subjects. For t 1/2Z of naloxone-3-glucuronide, on average there was no significant change between the renally impaired subjects and the healthy subjects. Abuse To avoid damage to the prolonged-release properties of the tablets, Targinact must not be broken, crushed or chewed, as this leads to a rapid release of the active substances. In addition, naloxone has a slower elimination rate when administered intranasally. Both properties mean that abuse of Targinact will not have the effect intended. In oxycodone-dependent rats, the intravenous administration of oxycodone hydrochloride / naloxone hydrochloride at a ratio of 2:1 resulted in withdrawal symptoms. 5.3 Preclinical safety data There are no data from studies on reproductive toxicity of the combination of oxycodone and naloxone. Studies with the single components showed that oyxcodone had no effect on fertility and early embryonic development in male and female rats in doses of up to 8 mg/kg body weight and induced no malformations in rats in doses of up to 8 mg/kg and in rabbits in doses of 125 mg/kg bodyweight. However, in rabbits, when individual fetuses were used in statistical evaluation, a dose related increase in developmental variations was observed (increased incidences of 27 presacral vertebrae, extra pairs of ribs). When these parameters were statistically evaluated using litters, only the incidence of 27 presacral vertebrae was increased and only in the 125 mg/kg group, a dose level that produced severe pharmacotoxic effects in the pregnant animals. In a study on pre- and postnatal development in rats F1 body weights were lower at 6 mg/kg/d when compared to body weights of the control group at doses which reduced maternal weight and food intake (NOAEL 2 mg/kg body weight). There were neither effects on physical, reflexological, and sensory developmental parameters nor on behavioural and reproductive indices. The standard oral reproduction toxicity studies with naloxone show that at high oral doses naloxone was not teratogenic and/or embryo/fetotoxic, and does not affect perinatal/postnatal development. At very high doses (800 mg/kg/day) naloxone produced increased pup deaths in the immediate post-partum period at dosages that produced significant toxicity in maternal rats (e.g., body weight loss, convulsions). However, in surviving pups, no effects on development or behaviour were observed. Long-term carcinogenicity studies with oxycodone/naloxone in combination or oxycodone as a single entity have not been performed. For naloxone, a 24-months oral carcinogenicity study was performed in rats with naloxone doses up to 100 mg/kg/day. The results indicate that naloxone is not carcinogenic under these conditions. Oxycodone and naloxone as single entities show a clastogenic potential in in vitro assays. No similar effects were observed, however, under in vivo conditions, even at toxic doses. The results indicate that the mutagenic risk of Targinact to humans at therapeutic concentrations may be ruled out with adequate certainty. Versie 1 juni 2016 Pagina 13 van 15

14 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Targinact 2.5 mg/1.25 mg Tablet core: Hydroxypropylcellulose Ethylcellulose Stearyl alcohol Lactose monohydrate Talc Magnesium stearate Tablet coat: Polyvinylalcohol, partially hydrolysed Titanium dioxide (E171) Macrogol 3350, Talc Iron oxide red (E172) Iron oxide yellow (E172) Targinact 15 mg/7.5 mg Tablet core: Hydroxypropylcellulose Ethylcellulose Stearyl alcohol Lactose monohydrate Talc Magnesium stearate Tablet coat: Polyvinylalcohol, partially hydrolysed Titanium dioxide (E171) Macrogol 3350 Talc Iron oxide black (E172) Iron oxide red (E172) Iron oxide yellow (E172) Targinact 30 mg/15 mg Tablet core: Povidone K30 Ethylcellulose Stearyl alcohol Lactose monohydrate Talc Magnesium stearate Tablet coat: Polyvinylalcohol, partially hydrolysed Titanium dioxide (E171) Macrogol 3350 Talc Iron oxide black (E172) Iron oxide red (E172) Iron oxide yellow (E172) Versie 1 juni 2016 Pagina 14 van 15

15 6.2 Incompatibilities Not applicable. 6.3 Shelf Life 3 years 6.4 Special precautions for storage Do not store above 25 C. 6.5 Nature and contents of container Child resisitant PVC/aluminium foil blisters Pack sizes: 10, 14, 20, 28, 30, 50, 56, 60, 98 or 100 tablets tabletshospital pack:100 (10 x 10) tablets Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. HOUDERVAN DE VERGUNNING VOOR HET IN DE HANDEL BRENGEN Mundipharma Pharmaceuticals B.V. Leusderend RC Leusden 8. NUMMER(S) VAN DE VERGUNNING VOOR HET IN DE HANDEL BRENGEN Targinact 2,5 mg/1,25 mg, tablet met verlengde afgifte RVG Targinact 15 mg/7,5 mg, tablet met verlengde afgifte RVG Targinact 30 mg/15 mg, tablet met verlengde afgifte RVG DATUM VAN EERSTE VERLENING VAN DE VERGUNNING: 30 DECEMBER DATUM VAN HERZIENING VAN DE TEKST Laatste gedeeltelijke wijziging betreft rubriek 4.8: 20 september 2016 Versie 1 juni 2016 Pagina 15 van 15